Introduction

  • Ketamine is a sedative used for patients with extreme/refractory undifferentiated agitation
  • Indications for utilizing ketamine for emergent sedation of agitated patients include

    • a. Patient poses and immediate threat to patient and healthcare provider safety (RASS +4)

    b. Failure and/or futility of alternative non-pharmacologic de-escalation strategies

    c. Absence of IV access

    d. Not a candidate for intramuscular antipsychotics and/or benzodiazepines due to onset of action

Clinical Detail

Pharmacology

PropertiesRapid acting general anesthetic producing cataleptic-like state due to antagonism of N-methyl-D-aspartate (NMDA) receptors in the central nervous system.
  • Ketamine also has significant analgesic/dissociative properties at lower doses
Dose2-5 mg/kg IM to a max single dose of 500 mg
1-2 mg/kg IV
AdministrationIM: Inject deep IM into large muscle (glute or vastus lateralis muscle)
IV: Administer over at least 60 seconds
Formulation10 mg/mL, 50 mg/mL, 100 mg/mL
*must use 100 mg/mL for IM administration to reduce volume
PK/PD (for amnestic effects)Onset: 3-5 mins IM; <1 minutes IV
Duration: 15-25 mins IM; 5-10 minutes IV
Bioavailability: 93% IM
Metabolism: Extensively through hematic N-demethylation
Elimination: Greater than 90% urine, <5% feces
Adverse Effects
  • Hypertension
  • Tachycardia
  • Hypersalivation
  • Nausea and vomiting
  • Laryngospasm
  • Emergence phenomenon during recovery phase
  • Increased muscle function (hyperactivity, twitching, rigidity)
Contraindications
  • Significant hypertension may be hazardous, ACS, ADHF, and unstable dysrhythmia
Warnings and Considerations
  • Rapid IV administration may increase risk of respiratory depression/apnea
  • Verify concentration of formulation
  • Caution in diagnosed schizophrenia
  • Hypotension in catecholamine depleted states
  • Pregnancy and lactation (crosses placenta)

Evidence

Author, YearDesign (Sample Size)Intervention & ComparisonOutcome
Lin et al., 2020Prospective, randomized, pilot (n=93)Ketamine 4 mg/kg IM or 1 mg/kg IV
Haloperidol 5-10 mg IM/IV + lorazepam 1-2 mg IM/IV		Ketamine achieved greater sedation within 5 and 15 minutes (22% vs 0% at 5 mins; 66% vs 7% at 15 mins)
Mankowitz et al., 2018Systematic review (n=650)Ketamine IV or IM
  • Mean time to sedation was 7.21 min and effective in 68.5% of patients
  • 30.5% of patients required intubation, but not all secondary to ketamine administration
Cole et al., 2016Prehospital prospective, observational (n=146)Haloperidol 10 mg IM
Ketamine 5 mg/kg IM
  • Median time to adequate sedation was faster with ketamine (5 min) vs haloperidol (17 min)
  • Intubation rates were higher with ketamine (39%) than haloperidol (4%), as well as more complications (49% vs 5%, respectively)
  • 38% hypersalivation in ketamine group
Isbister et al., 2016Subgroup analysis from DORM II study; prospective, observational (n=49)Ketamine as rescue treatment after
Droperidol alone
Droperidol + DZP or MDZ
Midazolam alone
  • Median time to sedation post-ketamine was 20 minutes (IQR 10-30)
  • 3 patients had adverse reactions after ketamine (vomiting n=2; desaturation n=1)
Riddell et al., 2016Prospective, observational (n=106)Ketamine
Lorazepam, midazolam, haloperidol, or benzodiazepine + haloperidol		Ketamine resulted in a greater number of patients with no agitation at 5 minutes than other medications
Scheppke et al., 2014Retrospective chart review (n=52)Ketamine ~4 mg/kg IM
*Recommended midazolam 2-2.5 mg IM or IV following ketamine for emergence reaction
  • 96% of patients obtained sedation, mean time to sedation was 2 minutes
  • 3 patients experienced significant respiratory depression
  • About ½ of patients received midazolam
Barbic et al., 2021Blinded, randomized controlled trial (n=80)Ketamine 5 mg/kg IM
Midazolam 5 mg IM + haloperidol 5 mg IM
  • Median time to adequate sedation was faster with ketamine (5.8 min) vs midazolam + haloperidol (14.7 min); difference 8.8 min (95% CI 3.0-14.5)
  • Adjusted Cox model favored ketamine (HR 2.43, 95% CI 1.43-4.12)
  • Serious adverse events: 5 (12.5%) ketamine vs 2 (5.0%) midazolam + haloperidol (difference 7.5%, 95% CI -4.8% to 19.8%)
Recent Evidence (2021-2026)
ACEP Clinical Policy, 2024Clinical policy / guideline (ACEP)Adult severe agitation (out-of-hospital & ED)Consensus clinical policy on the evaluation and management of severe agitation; recommends ketamine be considered as an option for rapid sedation when patient or staff safety is a primary concern
Siafis et al., 2026Systematic review + individual-participant-data network meta-analysis (18 trials, n=3,411)IM/IV rapid tranquilisation agents (antipsychotics, benzodiazepines, combinations vs haloperidol)
  • Antipsychotic-benzodiazepine combinations were among the most effective for sedation vs haloperidol monotherapy (moderate agitation OR 12.93; severe OR 4.86)
  • Haloperidol monotherapy least effective; overall confidence very low (imprecision/heterogeneity)
deSouza et al., 2022Systematic review + network meta-analysis (11 RCTs, n=1,142)ED rapid tranquilization agents
  • Ketamine ranked most likely superior for effectiveness (SUCRA 93%)
  • Droperidol-midazolam ranked safest (SUCRA 78.8%); a direct ketamine-vs-droperidol trial was recommended
Lipscombe et al., 2023Systematic review + meta-analysis (18 observational studies, n=3,476)Prehospital ketamine for acute agitation
  • Pooled prehospital intubation 1% (95% CI 0-2%) vs ED 19% (95% CI 11-30%); overall 16%
  • Most intubations occurred in the ED, not prehospital
Smith et al., 2026Systematic review (42 studies: RCT + observational + case series)Prehospital management of acute behavioural disturbance
  • Ketamine the most-studied and likely most effective sedation at 5 mg/kg IM (adequate sedation 79-98%)
  • Midazolam showed more side effects, particularly respiratory
Muldowney et al., 2024Retrospective cohort, out-of-hospital (n=376)Ketamine vs midazolam
  • Advanced airway management similar (ketamine 11% vs midazolam 12%; aOR 1.02, 95% CI 0.44-2.38)
  • No difference in ED intubation or mortality
Bernard et al., 2021Retrospective cohort, paramedic-administered (n=358; outcomes in 305)IM ketamine for severe agitation
  • Adequate sedation in 96.9% at a median of 5 min (IQR 3-7)
  • 14.8% intubated (2 prehospital); transient hypoxia 5.0%, hypersalivation 4.2%
Cunningham et al., 2021Retrospective pre/post cohort (n=292)Lower-dose (3 mg/kg) vs standard (4 mg/kg) IM ketamine
  • No difference in intubation or admission between dose protocols
  • Patients requiring a 2nd ketamine dose had higher intubation (41% vs 12.5%, P<.01)

DZP = diazepam; MDZ = midazolam

Conclusions

  • Ketamine has been shown to be effective with a quick time to sedation but is not without risks, including

    • respiratory depression

  • Used ketamine with caution in patients who have an underlying psychiatric disorder
  • Ketamine should be reserved for specific patient populations and as last line for patient/provider safety

References

  • Ketamine. Micromedex [Electronic version].
  • Lin M, et al. Am J Emerg Med. 2020. https://doi.org/10.1016/j.ajem.2020.04.013.
  • Mankowitz WL, et al. J Emerg Med. 2018;55(5):670-81.
  • Cole JB, et al. Clin Toxicol (Phila). 2016;54(7):556-562.
  • Isbister GK, et al. Ann Emerg Med. 2016;67(5):581-587.
  • Riddell J, et al. Am J Emerg Med. 2017. http://dx.doi.org/10.1016/j.ajem.2017.02.026
  • Scheppke KA, et al. WestJEM. 2014;15(7);736-41.
  • Barbic D, Andolfatto G, Grunau B, et al. Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial. Ann Emerg Med. 2021;78(6):788-795. doi:10.1016/j.annemergmed.2021.05.023
  • Bernard S, Roggenkamp R, Delorenzo A, et al. Use of intramuscular ketamine by paramedics in the management of severely agitated patients. Emerg Med Australas. 2021;33(5):875-882. doi:10.1111/1742-6723.13755
  • Cunningham C, Gross K, Broach JP, O'Connor L. Patient outcomes following ketamine administration for acute agitation with a decreased dosing protocol in the prehospital setting. Prehosp Disaster Med. 2021;36(3):276-282. doi:10.1017/S1049023X21000236
  • deSouza IS, Thode HC, Shrestha P, et al. Rapid tranquilization of the agitated patient in the emergency department: a systematic review and network meta-analysis. Am J Emerg Med. 2022;51:363-373. doi:10.1016/j.ajem.2021.11.011
  • Lipscombe C, Akhlaghi H, Groombridge C, et al. Intubation rates following prehospital administration of ketamine for acute agitation: a systematic review and meta-analysis. Prehosp Emerg Care. 2023;27(8):1016-1030. doi:10.1080/10903127.2022.2108178
  • Muldowney M, Counts CR, Maider MC, et al. A comparison of ketamine to midazolam for the management of acute behavioral disturbance in the out-of-hospital setting. Ann Emerg Med. 2024;85(5):411-420. doi:10.1016/j.annemergmed.2024.09.003
  • Thiessen MEW, Godwin SA, Hatten BW, et al; American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult out-of-hospital or emergency department patients presenting with severe agitation. Ann Emerg Med. 2024;83(1):e1-e30. doi:10.1016/j.annemergmed.2023.09.010
  • Smith F, Todd J, Avery P, Morton S. Prehospital management of acute behavioural disturbance: managing severe agitation in the prehospital setting—a systematic literature review. Emerg Med J. 2026. doi:10.1136/emermed-2025-215690
  • Siafis S, Philipona F, Nomura N, et al. Comparative effectiveness and safety of pharmacological treatments for rapid tranquilisation in emergency settings: a systematic review and individual participant data network meta-analysis. Lancet Psychiatry. 2026;13(7):567-580. doi:10.1016/S2215-0366(26)00097-0
Tags:ketamine acute agitation midazolam emergence reaction

Source PDF

PFP - ketamine for acute agitation 6 - Copy.pdf